3-substituted 3,4-dihydro-thieno[2,3-D]pyrimidine derivatives and production and use of the same

ABSTRACT

3-Substituted 3,4-dihydrothieno[2,3-d]pyrimidine derivatives of the formula I ##STR1## where R 1  and R 2  are a hydrogen atom or a C 1  -C 4  -alkyl group, 
     R 3  is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which is unsubstituted or mono- or disubstituted by halogen atoms, C 1  -C 4  -alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl, C 1  -C 4  -alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups and which may be fused to a benzene nucleus which may be unsubstituted or mono- or disubstituted by halogen atoms, C 1  -C 4  -alkyl, hydroxyl, trifluoromethyl, C 1  -C 4  -alkoxy, amino, cyano or nitro groups, and may contain 1 nitrogen atom, or to a 5- or 6-membered ring, which may contain 1-2 oxygen atoms, 
     A is NH or an oxygen atom, 
     Y is CH 2 , CH 2  --CH 2 , CH 2  --CH 2  --CH 2  or CH 2  --CH, 
     Z is a nitrogen atom, carbon atom or CH, it being possible for the linkage between Y and Z also to be a double bond, 
     and n is 2, 3 or 4, and the physiologically tolerated salts thereof.

This application is the National Stage Application of PCT/EP98/03230,which claims priority from German Application 19724980.9 filed Jun. 13,1997, and is filed under 37 CFR 1.78.

The invention relates to novel 3,4-dihydrothieno[2,3-d]pyrimidinederivatives, their preparation and use for producing active ingredientsfor drugs.

Classical antidepressants, and the newer selective serotonin reuptakeinhibitors (SSRIs), develop their antidepressant effect inter alia byinhibiting active reuptake of the transmitter into the presynaptic nerveendings. Unfortunately, the antidepressant effect thereof does not haveits onset until treatment has lasted at least 3 weeks, and, moreover,about 30% of patients are therapy-resistant.

Blockade of presynaptic serotonin autoreceptors increases, by abolishingnegative coupling, the serotonin release and thus the currenttransmitter concentration in the synaptic cleft. This increase in thetransmitter concentration is regarded as the principle of theantidepressant effect. This mechanism of action differs from previouslyknown antidepressants which activate both the presynaptic andsomatodendritic autoreceptors and therefore result in a delayed onset ofaction, only after desensitization of these autoreceptors. Directautoreceptor blockade bypasses this effect.

According to current knowledge, the presynaptic serotonin autoreceptoris of the 5-HT_(1B) subtype (Fink et al., Arch. Pharmacol. 352 (1995),451). Selective blockade thereof by 5-HT_(1B/D) antagonists increasesserotonin release in the brain: G. W. Price et al., Behavioural BrainResearch 73 (1996), 79-82; P. H. Hutson et al., Neuropharmacology Vol.34, No. 4 (1995), 383-392.

However, surprisingly, the selective 5-HT_(1B) antagonist GR 127 935reduces serotonin release in the cortex after systemic administration.One explanation might be stimulation of somatodendritic 5-HT_(1A)receptors in the raphe region by the released serotonin, which inhibitsthe firing rate of serotonergic neurons and thus serotonin release (M.Skingle et al., Neuropharmacology Vol. 34 No. 4 (1995), 377-382,393-402).

One strategy for bypassing the autoinhibitory effects in serotonergicareas of origin thus aims at blockade of presynaptic 5-HT_(1B)receptors. This hypothesis is supported by the observation that theeffect of paroxetine on serotonin release in the dorsal raphe nucleus ofthe rat is potentiated by the 5-HT_(1B) receptor antagonist GR 127 935(Davidson and Stamford, Neuroscience Letts., 188 (1995),41).

The second strategy includes blockade of both types of autoreceptors,namely the 5-HT_(1A) receptors, in order to intensify neuronal firing,and the 5-HT_(1B) receptors, in order to increase terminal serotoninrelease (Starkey and Skingle, Neuropharmacology 33 (3-4) (1994),393).

5-HT_(1B/D) antagonists, alone or coupled to a 5-HT_(1A) receptorantagonistic component, should therefore cause a greater increase inserotonin release in the brain and might therefore be associated withadvantages in the therapy of depressions and related psychologicaldisorders.

It has now been found that 3-substituted3,4-dihydrothieno-[2,3-d]pyrimidine derivatives of the formula I##STR2## where R¹ and R² are a hydrogen atom or a C₁ -C₄ -alkyl group,

R³ is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which isunsubstituted or mono- or disubstituted by halogen atoms, C₁ -C₄ -alkyl,trifluoromethyl, trifluoromethoxy, hydroxyl, C₁ -C₄ -alkoxy, amino,monomethylamino, dimethylamino, cyano or nitro groups and which may befused to a benzene nucleus which may be unsubstituted or mono- ordisubstituted by halogen atoms, C₁ -C₄ -alkyl, hydroxyl,trifluoromethyl, C₁ -C₄ -alkoxy, amino, cyano or nitro groups, and maycontain 1 nitrogen atom, or to a 5- or 6-membered ring, which maycontain 1-2 oxygen atoms,

A is NH or an oxygen atom,

Y is CH₂, CH₂ --CH₂, CH₂ --CH₂ --CH₂ or CH₂ --CH,

Z is a nitrogen atom, carbon atom or CH, it being possible for thelinkage between Y and Z also to be a double bond,

and n is 2, 3 or 4,

and the salts thereof with physiologically tolerated acids, havevaluable pharmacological properties.

Particularly preferred compounds are those where

R₁ and R² are methyl

R³ is o-methoxyphenyl, 1-naphthyl, 2-methoxy-1-naphthyl,2-methyl-1-naphthyl

A is an oxygen atom

Y is CH₂ --CH₂

Z is a nitrogen atom

and n is 2 and 3.

The novel compounds of the formula I can be prepared by reacting acompound of the formula II ##STR3## where R₁ [sic] has theabovementioned meaning, R³ is a cyano group or a C₁₋₃ -alkylcarboxylicester group, and R⁴ is C₁₋₃ -alkyl, with a primary amine of the formulaIII ##STR4## where R³ [sic] has the abovementioned meaning, andconverting the compound obtained in this way where appropriate into theaddition salt of a physiologically tolerated acid.

The reaction is expediently carried out in an inert organic solvent, inparticular a lower alcohol, eg. methanol or ethanol, or a cyclicsaturated ether, in particular tetrahydrofuran or dioxane.

The reaction is, as a rule, carried out at from 20 to 110° C., inparticular from 60 to 90° C., and is generally complete within 1 to 10hours.

Alternatively, a compound of the formula II ##STR5## where R₁ [sic] hasthe abovementioned meaning, R³ is a cyano group or a C₁₋₃-alkylcarboxylic ester group, and R⁴ is C₁₋₃ -alkyl, is reacted with aprimary amino alcohol of the formula IV ##STR6## in an inert solvent,preferably alcohols such as ethanol, at from 60° to 120° C., to give thecyclization product V (X=OH) ##STR7## which is subsequently convertedwith a halogenating agent, eg. thionyl chloride or hydrobromic acid, inan organic solvent such as a halohydrocarbon or without solvent at fromroom temperature to 100° C. into the corresponding halogen derivative V(X=Cl, Br).

Finally, the halogen derivative of the formula V (X=Cl, Br) is reactedwith an amine of the formula VI ##STR8## where Y, Z and R² have theabovementioned meanings, to give the novel final product of the formulaI. This reaction takes place best in an inert organic solvent,preferably toluene or xylene, in the presence of a base, eg. potassiumcarbonate or potassium hydroxide, at from 60° C. to 150° C.

The novel compounds of the formula I can be either recrystallized byrecrystallization from conventional organic solvents, preferably from alower alcohol such as ethanol, or purified by column chromatography.

The free 3-substituted pyrido[3',4':4,5]thieno[2,3-d]pyrimidinederivatives of the formula I can [lacuna] in a conventional way into theacid addition salts of [sic] a solution with the stoichiometric amountof the appropriate acid. Examples of pharmaceutically acceptable acidsare hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonicacid, sulfamic acid, maleic acid, fumaric acid, oxalic acid, tartaricacid or citric acid.

The invention accordingly also relates to a therapeutic compositionhaving a content of a compound of the formula I or its pharmacologicallyacceptable acid addition salt as active ingredient besides conventionalcarriers and diluents, and to the use of the novel compounds forcontrolling diseases.

The novel compounds can be administered orally or parenterally,intravenously or intramuscularly, in a conventional way.

The dosage depends on the age, condition and weight of the patient andon the mode of administration. As a rule, the daily dose of activeingredient is from about 1 to 100 mg/kg of body weight on oraladministration and from 0.1 to 10 mg/kg of body weight on parenteraladministration.

The novel compounds can be used in conventional solid or liquidpharmaceutical forms, eg. as uncoated or (film-)coated tablets,capsules, powders, granules, suppositories, solutions, ointments, creamsor sprays. These are produced in a conventional way. The activeingredients can for this purpose be processed with conventionalpharmaceutical aids such as tablet binders, bulking agents,preservatives, tablet disintegrants, flow regulators, plasticizers,wetting agents, dispersants, emulsifiers, solvents, release-slowingagents, antioxidants and/or propellant gases (cf. H. Sucker et al.:Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). Theadministration forms obtained in this way normally contain from 1 to 99%by weight of active ingredient.

The substances of the formula II to VI required as starting materialsfor synthesizing the novel compounds are known or can be synthesizedfrom similar starting materials by preparation methods described in theliterature (F. Sauter and P. Stanetty, Monatsh. Chem. 106(5), (1975),1111-1116; K. Gewald et al., Chem. Ber. 99, (1966) 94-100, German PatentApplication 196 36769.7).

The novel compounds have a high affinity for 5-HT_(1B), 5-HT_(1D) and5-HT_(1A) serotonin receptors. The affinity for these receptors ismoreover about the same, at least of the same order of magnitude.Furthermore, some of the novel compounds show good serotonin reuptakeinhibition, a principle which is implemented in most antidepressants.

These compounds are suitable as drugs for treating pathological statesin which the serotonin concentration is reduced and in which, as part oftherapy, it is wished to block specifically the activity of thepresynaptic 5-HT_(1B), 5-HT_(1A), 5-HT_(1D) receptors without having agreat effect on other receptors too. An example of a pathological stateof this type is depression.

The compounds of the present invention may also be useful for treatingmood disorders with a central nervous causation, such as seasonalaffective disorders and dysthymia. These also include anxiety statessuch as generalized anxiety, panic attacks, sociophobia,obsessive-compulsive neuroses and post-traumatic stress symptoms, memorydisturbances including dementia, amnesias and age-related memory loss,and psychogenic eating disorders such as anorexia nervosa and bulimianervosa.

The novel compounds can additionally be useful for treating endocrinedisorders such as hyperprolactinemia and for treating vasospasms(especially of the cerebral vessels), hypertension and gastrointestinaldisorders associated with motility and secretion disturbances. Anotherarea of use is for sexual disorders.

The following examples serve to illustrate the invention:

A Preparation of the Starting Materials

a) 2-Amino-3-carboethoxy-5-methyl-5-dimethylcarbamoylthiophene

82.8 ml, (775 mM [sic]) of ethyl cyanoacetate and 24.8 g (755 mM [sic])of sulfur powder were added to 100 g (775 mM [sic]) ofN,N-dimethylacetoacetamide in 400 ml of ethanol and then, while stirringvigorously and under a nitrogen atmosphere, 90 ml (647 mM [sic]) oftriethylamine were added dropwise. After 1 h, the mixture was refluxedfor 8 h and then left to stir at room temperature overnight. The mixturewas concentrated under reduced pressure, the residue was taken up in 2 lof water, the pH was adjusted to 9, and two extractions with methylenechloride were carried out. The organic phase was dried and concentratedand then the crude product (70 g) was purified by dissolving in 200 mlof boiling ethyl acetate. The solid which precipitated on stirringovernight was, after cooling in an ice bath, filtered off with suctionand washed several times with cold ethyl acetate. 39.0 g (20%) ofproduct were isolated as a gray solid of melting point 122-124° C.

b)2-Ethoxymethyleneamino-3-carboethoxy-4-methyl-5-dimethylcarbamoylthiophene

2.0 ml of acetic anhydride were added to 30.6 g (119 mM [sic]) of2-amino-3-carboethoxy-4-methyl-5-dimethylcarbamoylthiophene in 150 ml oftriethyl orthoformate and refluxed under nitrogen for 2 h. The mixturewas then completely evaporated in a rotary evaporator at 80° C. 35.6 g(96%) of crude product were isolated as a dark oil which is sufficientlypure for the next reaction.

c)3-(2-Hydroxyethyl)-5-methyl-6-dimethylcarbamoylthieno[2,3-d]pyrimidin-4-one

8.0 ml (133 mM [sic]) of ethanolamine were added to 35.6 g (114 mM[sic]) of2-ethoxymethyleneamino-3-carboethoxy-5-methyl-5-dimethylcarbamoylthiophene[sic] in 200 ml of ethanol and refluxed for 2 h. The mixture was thenconcentrated under reduced pressure. 29.9 g (93%) of dark viscous oilwere isolated.

d)3-(2-Chloroethyl)-5-methyl-6-dimethylcarbamoylthieno[2,3-d]pyrimidin-4-one

29.9 g (106 mM [sic]) of3-(2-hydroxyethyl)-5-methyl-6-dimethylcarbamoylthieno[2,3-d]pyrimidin-4-one in 200 ml of 1,2-dichloroethane were heated toreflux (slow dissolution) and then 12.7 ml (175 mM [sic]) of thionylchloride in 20 ml of 1,2-dichloroethane were added dropwise. Afterrefluxing for 1 h, the reaction mixture was cooled and concentrated. Thecrude product was partitioned between methylene chloride and water atpH=9. Drying and concentration of the organic phase resulted inisolation of 44.1 g (83%) of product as a dark oil which was purified bycolumn chromatography (silica gel, eluent ethyl acetate). 23.8 g (76%)of product were isolated with melting point 120-122° C.

Other C₁ -C₄ -mono- or dialkylcarbamoyl derivatives of formula II and Vcan be prepared as in methods a) to d).

e) N-(1-Naphthyl)piperazine

83.2 g (966 mM [sic]) of piperazine, 38.0 g (339 mM [sic]) of potassiumtert-butoxide and 50.0 g (241 mM [sic]) of 1-bromonaphthalene were addedto a mixture of 5.4 g (24.2 mM [sic]) of palladium acetate and 14.7 g(48.3 mM [sic]) of tri-o-tolylphosphine in 500 ml of xylene, and themixture was refluxed while stirring vigorously under a nitrogenatmosphere for 10 h. The mixture was then diluted with methylenechloride, the insoluble residues were filtered off, and the filtrate wasconcentrated. The crude product was purified by column chromatography(silica gel, eluent THF/methanol/ammonia 85/13/2). 21.5 g (42%) ofproduct were isolated with melting point 84-86° C.

f) N-(2-Methyl-1-naphthyl)piperazine

14.7 g (82.7 mM [sic]) of bis(2-chloroethyl)amine ×HCl were added to13.0 g (82.7 mM [sic]) of 1-amino-2-methylnaphthalene in 100 ml ofchlorobenzene and refluxed under nitrogen for 90 h. The mixture was thenconcentrated and partitioned between methylene chloride and water atpH=9, and the organic phase was dried and concentrated. The crudeproduct was purified by column chromatography (silica gel,eluent/THF/methanol/ammonia 85/13/2. 11.6 g (62%) of product wereisolated.

g) 4-Piperazin-1-ylisoquinoline

4.51 g (21.7 mM [sic]) of 4-bromoisoquinoline, 4.65 g (25.0 mM [sic]) oft-butyl piperazine-N-carboxylate, 0.1 g (0.11 mM [sic]) oftris(dibenzylideneacetone)dipalladium, 0.11 g (0.18 mM [sic]) of2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 2.92 g (30.4 mM [sic])of sodium t-butoxide were mixed in 50 ml of toluene and stirred at 75°C. for 2 h. The reaction mixture was added to ice/sodium chloride andextracted with ethyl acetate, the organic phase was dried over sodiumsulfate and the solvent was removed in a rotary evaporator. The productcrystallized out and was filtered off with suction and washed withpentane. 5.5 g (81%) of the Boc-protected piperazine (melting point:111° C.) were obtained. 5.2 g (16.6 mM [sic]) of this substance weretaken up in 17 ml of dichloromethane and, at 0° C., taken up slowly in17 ml of dichloromethane [sic], and, at 0° C., 17 ml (0.22 mM [sic]) oftrifluoroacetic acid were slowly added. The mixture was left to stir at0° C. for 4 h, poured into ice-water and extracted with dichloromethane.The aqueous phase was filtered, made alkaline and extracted withdichloromethane. Drying over sodium sulfate and substantial removal ofthe solvent were followed by dilution with diethyl ether andprecipitation of the hydrochloride with ethereal hydrochloric acid. 3.2g (67%) of the product were obtained with melting point 293-294° C.

Further piperazine derivatives (see Examples) not disclosed in theliterature (cf. also German Patent Application 19636769.7) were preparedas in e), f) and g).

B Preparation of the Final Products EXAMPLE 1

3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methoxy-phenyl)-1-piperazinyl)ethyl]thieno(2,3-d]pyrimidin-4-one [sic]

1.9 g (8.0 mM [sic]) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)-piperazinewere added to 2.4 g (7.8 mM [sic]) of2-ethoxymethyleneamino-3-carboethoxy-4-methyl-5-dimethylcarbamoylthiophene in 30 ml of ethanol and refluxed for 2 h. The productcrystallized out after standing overnight and was filtered off withsuction and washed with a little ethanol. 2.2 g (62%) of product wereisolated with melting point 188-190° C.

EXAMPLE 2

3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2,3-dimethyl-phenyl)-1-piperazinyl)ethy1.1 g (5.0 mM [sic]) of 1-(2,3-dimethylphenyl)piperazine hydrochlorideand 1.54 ml (11 mM [sic]) of triethylamine were added to 1.5 g (5.0 mM[sic]) of3-(2-chloroethyl)-5-methyl-6-dimethylcarbamoylthieno[2,3-d]pyrimidin-4-onein 15 ml of dimethylformamide and heated at 125° C. under nitrogen for atotal of 3 h. Pouring into water was followed by extraction with ethylacetate, the organic phase was extracted with dilute hydrochloric acidat pH=2, and the aqueous phase resulting from this was made basic withdilute sodium hydroxide solution. The crude product was extracted withdichloromethane and, after drying over sodium sulfate, the solvent wasremoved under reduced pressure. The oily residue was crystallized from alittle methanol and filtered off with suction. It was possible in thisway to obtain 0.7 g (31%) of product with melting point 160-161° C.

The following were prepared as in Examples 1 and 2:

3.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(1-naphthyl)-1-piperazinyl)ethyl]thieno[2,3-d]pyrimidin-4-one,melting point 190-191° C.

4.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methyl-1-napththyl)-1-piperazinyl)ethyl]thieno[2,3-d]pyrimidin-4-one,melting point 178-180° C.

5.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methoxy-1-naphthyl)-1-piperazinyl)ethyl]thieno[2,3-d]pyrimidin-4-one×H₂O, melting point 153-155° C. (decomposition)

6.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methylphenyl)-1-piperazinyl)ethyl]thieno[2,3-d]pyrimidin-4-one

7.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(3-tri-fluoromethylphenyl)-1-piperazinyl)ethyl]thieno[2,3-d]-pyrimidin-4-one,melting point 146° C.

8.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-chloro-phenyl)-1-piperazinyl)ethyl]thieno[2,3-d]pyrimidin-4-one,

9.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-pyrimidin-2-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one×2HCl×4H₂ O, melting point 180-182° C. (decomposition)

10.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-pyridin-2-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

11.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-quinolin-2-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one,

12.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(3,5-dichlorophenyl)-1-piperazinyl)ethyl]thieno[2,3-d]pyrimidin-4-one

13.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-tetralin-5-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one,melting point 174° C.

14.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-indan-4-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one,melting point 153° C.

15.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-cyanophenyl)-1-piperazinyl)ethyl]thieno[2,3-d]pyrimidin-4-one,melting point 210° C. (hydrochloride)

16.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-isoquinolin-4-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

17.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[3-(4-pyrimidin-2-ylpiperazin-1-yl)propyl]thieno[2,3-d]pyrimidin-4-one,×2 HCl×2 H₂ O, melting point 209-211° C. (decomposition)

18.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methoxyphenyl)-1-piperidinyl)ethyl]thieno[2,3-d]pyrimidin-4-one

19.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methoxyphenyl)-3,4-dihydro-1-piperidinyl)ethyl]thieno[2,3-d]-pyrimidin-4-one[sic]

20.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-naphth-1-ylpiperidin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

21.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2-methoxy-1-naphthyl)-3,4-dehydro-1-piperidinyl)ethyl]thieno-[2,3-d]pyrimidin-4-one

22.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-naphth-1-yl-1,4-hexahydro-1,4-diazepin-1-yl)ethyl]thieno-[2,3-d]pyrimidin-4-one,melting point 225-230° C. (hydrochloride)

23.3,4-Dihydro-5-methyl-6-carbamoyl-3-[2-(4-(1-naphthyl)-1-piperazinyl)ethyl]thieno[2,3-d]pyrimidin-4-one

24.3,4-Dihydro-5-methyl-6-carbamoyl-3-[2-(4-pyrimidin-2-yl-piperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

25.3,4-Dihydro-5-methyl-6-diethylcarbamoyl-3-[2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl]thieno[2,3-d]pyrimidin-4-one

26.3,4-Dihydro-5-methyl-6-diethylcarbamoyl-3-[2-(4-(1-naphthyl)-1-piperazinyl)ethyl]thieno[2,3-d]pyrimidin-4-one

27.3,4-Dihydro-5-methyl-6-diethylcarbamoyl-3-[2-(4-pyrimidin-2-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one

28.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-quinazolin-4-ylpiperazin-1-yl)ethyl]thieno[2,3-d]pyrimidin-4-one,melting point 295-300° C. (hydrochloride)

29.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2,4-dimethoxyphenyl)-1-piperazinyl)ethyl]thieno[2,3-d]pyrimidin-4-one,melting point 170-171° C.

30.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-(2,5-dimethylphenyl)-1-piperazinyl)ethyl]thieno[2,3-d]pyrimidin-4-one,melting point 90-91° C.

31.3,4-Dihydro-5-methyl-6-dimethylcarbamoyl-3-[2-(4-naphth-1-yl-3,4-dehydro-1-piperidinyl)ethyl]thieno[2,3-d]-pyrimidin-4-one,MS: m⁺ =509.1

We claim:
 1. A 3-substituted 3,4-dihydrothieno[2,3d]pyrimidinederivative of the formula I ##STR9## where R¹ and R² are a hydrogen atomor a C₁ -C₄ -alkyl group,R³ is a phenyl, pyridyl, pyrimidinyl orpyrazinyl group which is unsubstituted or mono- or disubstituted byhalogen atoms, C₁ -C₄ -alkyl, trifluoromethyl, trifluoromethoxy,hydroxyl, C₁ -C₄ -alkoxy, amino, monomethylamino, dimethylamino, cyanoor nitro groups and which may be fused to a benzene nucleus which may beunsubstituted or mono- or disubstituted by halogen atoms, C₁ -C₄ -alkyl,hydroxyl, trifluoromethyl, C₁ -C₄ -alkoxy, amino, cyano or nitro groups,and may contain 1 nitrogen atom, or to a 5- or 6-membered ring, whichmay contain 1-2 oxygen atoms, A is NH or an oxygen atom, Y is CH₂, CH₂--CH₂, CH₂ --CH₂ --CH₂ or CH₂ --CH, Z is a nitrogen atom, carbon atom orCH, or optionally the linkage between Y and Z can be a double bond,or nis 2, 3 or 4, and the physiologically acceptable salts thereof.
 2. Acompound as claimed in claim 1, whereinR¹ and R² are methyl, R³ iso-methoxyphenyl, 1-naphthyl, 2-methoxy-1-naphthyl, 2-methyl-1-naphthyl Ais an oxygen atom Y is CH₂ --CH₂ Z is a nitrogen atomor n is 2 and
 3. 3.A pharmaceutical composition for the treatment of depression and relateddisorders comprising an effective amount compound of claims 1 or
 2. 4. Amethod for the treatment of depression and related disorders whichcomprises administering to the patient a composition comprising aneffective amount of a compound of claims 1 or
 2. 5. The method of claim4 wherein the compound acts as selective 5HT_(1B) and 5HT_(1A)antagonist.
 6. The method of claim 5 wherein the selective serotoninantagonism is supplemented by inhibition of serotonin uptake.